Compounds and methods for use thereof in the treatment of cancer

ABSTRACT

Benzimidazole derivatives and salts and prodrugs thereof are disclosed, together with methods for the treatment of cancers or viral infections in warm blooded animals by administration of these compounds. Such compounds may be used in combination with a chemotherapeutic agent and/or a potentiator.

The present application is a continuation-in-part of U.S. applicationSer. No. 08/857,811, filed May 16, 1997 U.S. Pat. No. 6,506,783, entiredisclosure of which is incorporated by reference herein.

TECHNICAL FIELD

The present invention relates to benzimidazole derivatives and their usefor the treatment of cancer or a viral infection in warm bloodedanimals, particularly in humans and other mammals. The methods may usesuch a compound in combination with a potentiator or a chemotherapeuticagent.

BACKGROUND OF THE INVENTION

Cancers are a leading cause of death in animals and humans. The exactcause of cancer is not known, but links between certain activities suchas smoking or exposure to carcinogens and the incidence of certain typesof cancers and tumors has been shown by a number of researchers.

Many types of chemotherapeutic agents have been shown to be effectiveagainst cancers and tumor cells, but not all types of cancers and tumorsrespond to these agents. Unfortunately, many of these agents alsodestroy normal cells. The exact mechanism for the action of thesechemotherapeutic agents are not always known.

Despite advances in the field of cancer treatment the leading therapiesto date are surgery, radiation and chemotherapy. Chemotherapeuticapproaches are said to fight cancers that are metastasized or ones thatare particularly aggressive. Such cytocidal or cytostatic agents workbest on cancers with large growth factors, i.e., ones whose cells arerapidly dividing. To date, hormones, in particular estrogen,progesterone and testosterone, and some antibiotics produced by avariety of microbes, alkylating agents, and anti-metabolites form thebulk of therapies available to oncologists. Ideally cytotoxic agentsthat have specificity for cancer and tumor cells while not affectingnormal cells would be extremely desirable. Unfortunately, none have beenfound and instead agents that target especially rapidly dividing cells(both tumor and normal) have been used.

Clearly, the development of materials that would target cancer cells dueto some unique specificity for them would be a breakthrough.Alternatively, materials that were cytotoxic to cancer cells whileexerting mild effects on normal cells would be desirable.

Human Immunodeficiency Virus (HIV), the etiological agent for AIDS(acquired immune deficiency syndrome), is a member of the lentiviruses,a subfamily of retroviruses. HIV integrates its genetic information intothe genome of the host. Most importantly, HIV infects and invades cellsof the immune system; it breaks down the body's immune system andrenders the patient susceptible to opportunistic infections andneoplasms. HIV-1 is cytopathic for T4 lymphocytes, cells of the immunesystem that express the cell surface differentiation antigen CD4. Inaddition to CD4+T cells, the host range of HIV includes cells of themononuclear phagocytic lineage, including blood monocytes, tissuemacrophages, Langerhans cells of the skin and dendritic reticulum cellswithin lymph nodes.

Precursor cells in the bone marrow are released into the blood in animmature circulating form known as monocytes. Monocytes use the bloodstrictly as a transport medium. Once they arrive where they're going tobe used, they leave the blood and complete differentiation intomacrophages. Cells of the monocyte/macrophage lineage are a major targetpopulation for infection with HIV in the body and are thought to providereservoirs of virus for disseminating infection throughout the body. HIVis also neurotropic, capable of infecting monocytes and macrophages inthe central nervous system causing severe neurologic damage. They caninteract and fuse with CD4-bearing T cells, causing T cell depletion andthus contributing to the pathogenesis of AIDS.

Progression from HIV infection to AIDS is primarily determined by theeffects of HIV on the cells that it infects, including CD4+T lymphocytesand macrophages. In turn, cell activation, differentiation andproliferation regulate HIV infection and replication in those cells. HIVand other lentiviruses can proliferate in nonproliferating, terminallydifferentiated macrophages and growth-arrested T lymphocytes. Thisability of lentiviruses, including HIV, to replicate in nonproliferatingcells, particularly in macrophages, is believed to be unique amongretroviruses.

Due to the above-mentioned problems in the art, the present inventorshave sought improvements and provide such improvements herein.

Carbendazim or 2-methoxycarbonylaminobenzimidazole has been studied as acancer treatment. See U.S. Pat. No. 5,767,138 issued Jun. 16, 1998 to J.B. Camden. Carbendazim metabolizes in the body through the hydroxylationof the benzene ring, primarily in the 5-position. The metabolite is notas active in the treatment of cancer as the2-methoxycarbonylaminobenzimidazole. Moreover, the benzimidazoles arenot easily soluble in water. The derivatives described herein are moresoluble and still maintain cytoxicity comparable to carbendazim.

SUMMARY OF THE INVENTION

The compounds of the present invention are represented by the followingformula A:

wherein

R is —COOR₁, —CONR₁R₂, —OCOR₁ or —NHCOR₁;

R₁ is alkyl, haloalkyl, hydroxyalkyl, alkenyl, haloalkenyl, cycloalkyl,cycloalkalkyl, heterocycloalkyl, heterocycloalkalkyl, substituted orunsubstituted phenyl, substituted or unsubstituted phenylamino,substituted or unsubstituted benzyl, alkoxyalkyl, poly(alkoxy)alkyl,hydroxyalkoxyalkyl, hydroxypoly(alkoxy)alkyl, haloalkoxyalkyl,halopoly(alkoxy)alkyl, or aminoalkyl; and

R₂ is hydrogen or alkyl.

The phenyl group, the phenylamino group, or the benzyl group mayoptionally be substituted with one or more nitro, carboxy, hydroxy,alkyl, alkoxy, or halide substituents.

Pharmaceutically acceptable salts of the benzimidazole derivatives offormula A are also included in the present invention. Further includedin the invention are the prodrugs of the compounds of formula A.

In one embodiment of the invention, the benzimidazole derivatives of theinvention are of the formula A-1:

and preferably the compounds are of formula A-1 where R is —OCOR₁, morepreferably where R₁ is substituted or unsubstituted phenyl.

In another embodiment of the invention, the benzimidazole derivativesare of the formula A-2:

In another embodiment of the invention, the benzimidazole derivativesare of the formula A-3:

In another embodiment of the invention, the benzimidazole derivativesare of the formula A4:

In another embodiment of the invention, the benzimidazole derivativesare of the formula A-5:

Methods are provided by the present invention for treatment of warmblooded animals, and in particular, humans and other mammals, that areaffected by cancer or viral infection, the methods comprisingadministering a therapeutically effective amount of a benzimidazolederivative of formula A, or a salt or a prodrug thereof, to the animal.

DETAILED DESCRIPTION OF THE INVENTION

A. Definitions

The term “alkyl” refers to a fully saturated monovalent hydrocarbonradical of 1 to 12 carbon atoms. It may be straight-chain or branched.Preferred are those alkyl groups containing 1 to 10 carbon atoms, with 2to 8 carbon atoms particularly preferred.

The term “alkenyl” refers to an unsaturated monovalent hydrocarbonradical of 2 to 12 carbon atoms containing only carbon and hydrogen andhaving one or more double bonds. It may be straight-chain or branched.Preferred are those alkenyl groups containing 2 to 10 carbon atoms, with2 to 8 carbon atoms particularly preferred.

The term “alkoxy” means the group —OR′ wherein R′ is alkyl. Preferredare alkoxy groups having 1 to 10 carbon atoms, more preferably 2 to 8carbon atoms.

The term “alkoxyalkyl” refers to an alkoxy group covalently attached toan alkyl group. The alkoxy group contains from 1 to 12, preferably from1 to 6 carbon atoms. The alkoxy group may be substituted with one ormore hydroxyl groups (an “hydroxyalkoxyalkyl”) or with one or morehalogen atoms (a “haloalkoxyalkyl”); preferably the hydroxyl or halogenis on the terminal end of the alkoxyalkyl substituent

The term “poly(alkoxy)alkyl” denotes 2 to 200, preferably 2 to 20,alkoxy groups covalently linked in either a linear or a branchedconfiguration and attached to an alkyl group. Linear poly(alkoxy)alkylmoieties have a structure such as

—(CH₂)_(m)—O—(CH₂)_(m)—O—(CH₂)_(m)—. . . —O—C_(m)H_(2m+1), where “m” isan integer, the same or different along the length of the chain.Branched moieties have two or more (—O—(CH_(t))_(m)—) groups bound to acommon third (—O—(CH_(t))_(m)—) group, where “t” has a value that isindependently selected from 0, 1 and 2 for each (CH_(t))_(m) group.Linear configurations are preferred. The number of repeating(—O—(CH_(t))_(m)—) groups within a substituent may be up to 200,preferably from 2 to 20, more preferably from 2 to 7, and mostpreferably is 2-5. The individual alkoxy groups may be the same ordifferent, and individual alkoxy groups preferably contain from 1 to 6carbon atoms each, and most preferably from 1 to 3 carbon atoms each. Apresently preferred poly(alkoxy)alkyl is —(CH₂)_(y)—(OCH₂CH₂)_(x)—OCH₃or

—(CH₂)_(y)—(OCH₂CH)_(x)—OCH₂CH₃, where y=1-4 and x=1-100, preferably1-10, preferably, 2-5. The individual alkoxy groups may be substitutedwith one or more hydroxyl groups (an “hydroxypoly(alkoxy)alkyl”) or withone or more halogen atoms (a “halopoly(alkoxy)alkyl”); preferably thehydroxyl or halogen is on the terminal end of the poly(alkoxy)alkylsubstituent.

“Heterocyclo” designates a heterocyclic group; that is, a closed-ringstructure, usually of either 5 or 6 members, in which one or more of theatoms in the ring is an element other than carbon, such as for examplesulfur, nitrogen, or oxygen. A heterocyclic group may be, but is notlimited to, pyridine, pyrrole, furan, thiophene, morpholine, and purine,optionally substituted with one or more nitro, carboxy, sulfonic acid,hydroxy, alkyl, alkoxy, or halide substituents.

The term “amino” refers to primary amines (—NH₂), secondary amines(—NHR′), and tertiary amines (—NR′R″), where R′ and R″ are the same ordifferent substituent groups, such as alkyl, alkenyl, halogen, hydroxy,and the like.

“Independently” signifies that two or more of the groups immediatelypreceding the term are either identical or different; i.e., selection ofone from the list following the term does not affect selection of theother(s).

“Substituted” encompasses both single and multiple substitutions, thelatter including multiple substitutions by the same substituent as wellas mixtures of different substituents.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances in which said event or circumstanceoccurs and instances in which it does not. For example, “optionallysubstituted phenyl” means that the phenyl may or may not be substitutedand that the description includes both unsubstituted phenyl and phenylwherein there is substitution. As another example, “optionally” followedby “converting the free base to the acid addition salt” means that suchconversion may or may not be carried out in order for the processdescribed to fall within the invention, and the invention includes thoseprocesses wherein the free base is converted to the acid addition saltand those processes in which it is not.

As used herein, “a therapeutically effective amount” means theconcentration or quantity or level of the compound of the presentinvention that can attain a particular medical end, such as control ordestruction of cancer cells, virally-infected cells, or viruses withoutproducing unacceptable toxic symptoms. The term “safe and effectiveamount” refers to the quantity of a component which is sufficient toyield a desired therapeutic response without undue adverse side effects(such as toxicity, irritation, or allergic response) commensurate with areasonable benefit/risk ratio when used in the manner of this invention.The specific “safe and effective amount” will vary with such factors asthe particular condition being treated, the physical condition of thepatient, the type of mammal being treated, the duration of thetreatment, the nature of concurrent therapy (if any), and the specificformulations employed and the structure of the compounds or its salts.

As used herein, a “pharmaceutical addition salt” or “pharmaceuticallyacceptable salt” is a salt of the benzimidazole derivative compound withan organic or inorganic acid. These preferred acid addition salts arechlorides, bromides, sulfates, nitrates, phosphates, sulfonates,formates, tartrates, maleates, malates, citrates, benzoates,salicylates, ascorbates, and others known to those of ordinary skill inthe art.

As used herein, the term “prodrug” refers to a form of a benzimidazolederivative compound that has minimal therapeutic activity until it isconverted to its desired biologically active form. A prodrug is acompound having one or more functional groups or carriers covalentlybound thereto, which functional groups or carriers are removed from thecompound by metabolic processes within the body to form the respectivebioactive compound.

As used herein, the term “metabolite” refers to the break-down or endproduct of a benzimidazole derivative compound or its salt produced bymetabolism or biotransformation in the animal or human body; e.g.,biotransformation to a more polar molecule such as by oxidation,reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman,“The Pharmacological Basis of Therapeutics” 8^(th) Ed., Pergamon Press,Gilman et al. (eds), 1990 for a discussion of biotransformation). Asused herein, the metabolite of a benzimidazole derivative compound orits salt may be the biologically active form of the compound in thebody. An assay for activity of a metabolite of a benzimidazolederivative of the present invention is known to one of skill in the artin light of the present disclosure, for example, testing for efficacyagainst a virus in vitro or in vivo.

As used herein, a “subject in need thereof” is a warm blooded animalhaving cancer or having a viral infection.

As used herein, “cancer” refers to all types of cancers, or neoplasms orbenign or malignant tumors. In one embodiment, those cancers that attacknormal healthy blood cells or bone marrow are contemplated by thepresent invention. Preferred cancers for treatment using methodsprovided herein include carcinoma, sarcoma, lymphoma, or leukemia. By“carcinoma” is meant a benign or malignant epithelial tumor andincludes, but is not limited to, breast carcinoma, prostate carcinoma,non-small cell lung carcinoma, colon carcinoma, CNS carcinoma, melanomacarcinoma, ovarian carcinoma, or renal carcinoma. A preferred host is ahuman host.

A “viral infection” as used herein means an infection due to a DNA virusor an RNA virus (retrovirus). Examples of a double-stranded DNA virusare the Herpes virus and the influenza virus. Human immunodeficiencyvirus (HIV) is a prototype for retroviruses, i.e., viruses that usereverse transcription to replicate. However, certain DNA viruses use, inpart, reverse transcription mechanisms to replicate such as, forexample, the Hepatitus B virus. “Viruses” include retroviruses such asHIV or HTLV, influenza, rhinoviruses, herpes, hepatitis, or the like.

As used herein, a benzimidazole derivative of formulas A and A-1 throughA-5, or a pharmaceutical salt thereof or a prodrug thereof, are“compounds of the present invention.” Such compounds are further setforth under B infra.

As used herein, “chemotherapeutic agents” includes DNA-interactiveagents, antimetabolites, tubulin-interactive agents, hormonal agents andothers, such as asparaginase or hydroxyurea, and are as further setforth under D infra.

As used herein, “potentiators” are materials that affect the immunesystem or enhance the effectiveness of a compound of the presentinvention and are further set forth under E herein.

Following long-standing patent law convention, the terms “a” and “an”mean “one or more” when used in this application, including the claims.

B. Benzimidazole Derivatives

The benzimidazole derivatives of the present invention are those offormula A, as set forth above. Presently preferred compounds are thoseof formulas A-1 through A-5.

Pharmaceutically acceptable salts of the benzimidazole compounds areconsidered within the scope of compounds of the present invention. Theyare salts with an organic or inorganic acid. Preferred acid additionsalts are chlorides, bromides, sulfates, nitrates, phosphates,sulfonates, formates, tartrates, maleates, malates, citrates, benzoates,salicylates, ascorbates, or the like. Such salts may be synthesized fromthe compound of the present invention, or derivative thereof, thatcontains a basic or acidic moiety, by conventional chemical methods.Generally, such salts may be prepared by reacting a free acid or baseform of the compound, or derivative thereof, with a stoichiometricamount of the appropriate base or acid in water or in an organicsolvent, or in a mixture of the two. Generally, nonaqueous media likeether, ethyl acetate, ethanol, isopropanol, or acetonitrile arepreferred. Further suitable salts may be found in Remington: The Scienceand Practice of Pharmacy, 19th ed., Mack Publishing Company, Easton,Pa., 1995, p. 1457.

Pharmaceutically acceptable salts of the compounds of the presentinvention include conventional non-toxic salts or the quaternaryammonium salts of the compounds or derivatives formed, for example, fromnon-toxic inorganic or organic acids. For example, such conventionalnon-toxic salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, orthe like; and salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, or the like.Preferred acid addition salts are chlorides, bromides, sulfates,nitrates, phosphates, sulfonates, formates, tartrates, maleates,malates, citrates, benzoates, salicylates, ascorbates, or the like. Apresently preferred salt is the hydrochloride salt.

Further included within the scope of the compound, or salts thereof,useful for the present invention are prodrugs thereof. As used herein, a“prodrug” is a drug covalently bonded to a carrier wherein release ofthe drug occurs in vivo when the prodrug is administered to a mammaliansubject. Prodrugs of the compounds of the present invention are preparedby modifying functional groups present in the compounds in such a waythat the modifications are cleaved, either in routine manipulation or invivo, to yield the desired compound. Prodrugs include compounds whereinhydroxy, amine, or sulfhydryl groups are bonded to any group that, whenadministered to a mammalian subject, is cleaved to form a free hydroxyl,amino, or sulfhydryl group, respectively. Examples of prodrugs include,but are not limited to, acetate, formate, or benzoate derivatives ofalcohol or amine functional groups in the compounds of the presentinvention; phosphate esters, dimethylglycine esters, aminoalkylbenzylesters, aminoalkyl esters or carboxyalkyl esters of alcohol or phenolfunctional groups in the compounds of the present invention; or thelike.

Synthetic Reaction Parameters

The terms “solvent”, “inert organic solvent” and “inert solvent” mean asolvent that is passive or non-reactive under the conditions of thereaction being described in conjunction therewith (including, forexample, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”),dimethylformamide (“DMF”), chloroform, methylene chloride (ordichloromethane), diethyl ether, methanol, pyridine, and the like).Unless specified to the contrary, the solvents used in the reactions ofthe present invention are inert organic solvents.

The reaction temperature can vary widely depending on the reactivity ofthe reactants. However, the temperature should not be so high as todecompose the reactants or so low as to cause inhibition of thecondensation or freezing of the solvent. Unless specified to thecontrary, the reactions described herein take place at atmosphericpressure over a temperature range from the temperature of dry ice toabout 100° C., more preferably from about 10° C. to about 50° C., andmost preferably at “room” or “ambient” temperature (“RT”), e.g. about20° C.

Unless otherwise specified, the reaction times and conditions areintended to be approximate.

The time required for the reactions herein will depend to a large extenton the temperature being used and the relative reactivities of thestarting materials. Therefore, the reaction time can vary greatly, forexample from about five minutes to about two days. Various knowntechniques such as different types of chromatography, especially thinlayer chromatography (“TLC”), gas chromatography (“GC”), or opticalspectroscopy can be used to follow the progress of the reaction by thedisappearance of the starting compound(s).

Isolation and purification of the compounds and intermediates describedherein can be effected, if desired, by any suitable separation orpurification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography,thick-layer chromatography, centrifugal chromatography, or preparatoryHPLC, or a combination of these procedures. Specific illustrations ofsuitable separation and isolation procedures can be found by referenceto the examples hereinbelow. However, other equivalent separation orisolation procedures can, of course, also be used.

Synthesis of Compounds of Formula A

The compounds of the invention are prepared by modification to thebenzimidazole carbamate nucleus:

In one synthetic process, the known 5(6) carboxylic acid benzimidazolecarbamate (101) is treated with thionyl chloride in benzene to activatethe carboxyl group, then is derivatized with alcohols or amines to formcompounds of formula A-2 (102)or A-3 (103) (Reaction Scheme 1),following procedures known to those of skill in the art.

Similarly, to prepare compounds of Formula A-1 where R is —COOR₁ or—CONR₁R₂, the 4(7) carboxylic acid benzimidazole carbamate is treatedwith thionyl chloride in benzene to activate the carboxyl group, then isderivatized with alcohols or amines following the procedures of ReactionScheme 1 to form the compounds of formula A-1 where R is —COOR₁ or—CONR₁R₂.

To prepare compounds of Formula A-5, the known 5(6)-amino benzimidazolecarbamate (201) is reacted with a carbonyl chloride (202) to give the5(6)-carboxamide benzimidazole derivatives of formula A-5 (203)(Reaction Scheme 2), following procedures known to those of skill in theart.

In a similar manner, to prepare compounds of Formula A-1 or A4, theknown 4(7) or 5(6) hydroxylated benzimidazole carbamate (301 or 302,respectively) is reacted with a carbonyl chloride (303) to give the 4(7)or the 5(6) carboxy benzimidazole derivatives of formula A-2 (304) orformula A-4 (305), respectively (Reaction Scheme 3), followingprocedures known to those of skill in the art.

Presently Preferred Embodiments

In one embodiment of the present invention, presently preferredbenzimidazole derivatives are those of Formula A-1 where R is selectedfrom those groups listed in Table 1.

Solubility is based on a standard measure used in medicinal chemistry,the octanol-water partition coefficient, LogP, Lower Log) valuesindicate higher aqueous solubility. There are a variety of methods toestimate this value for a proposed structure using computercalculations. The below LogP solubility values were determined using theatom typing method of Ghose, Pritchett et al. (J. Comput. Chem 9(1):80-90, 1988). Carbendazim has a LogP of 1.302.

TABLE 1 Cpd. No. R LogP 1-1 —OCOCH₂CH(CH₃)CH₂C(CH₃)₃ 3.712 1-2—OCOPh(3-OCH₃-4-OCH₃-5-OCH₃) 1.955 1-3 —COOCH₂CH═CH₂ — 1-4 —COOCH₂CCl₃ —1-5 —CONHCH₂CH═CH₂ — 1-6 —CONHCH₂CCl₃ —

In another embodiment of the invention, presently preferredbenzimidazole derivatives are those of Formula A-2 where R₁ and R₂ areselected from those groups listed in Table 2:

TABLE 2 Cpd. No. R₁ R₂ LogP 2-1 —CH₂CH₂CH₂N(CH₂CH₃)₂ H 1.098 2-2—CH₂CH₂-morpholino H 0.018 2-3 —CH(CH₃)CH₂CH₃ H 1.606 2-4—CH₂-(2-tetrahydrofuryl) H 0.613 2-5 —CH₂CH₂CH(CH₃)₂ H 1.920 2-6—CH(CH₃)CH₂CH(CH₃)₂ H 2.333 2-7 —CH₂CH₂C(CH₃)₃ H 2.353 2-8—CH₂CH(CH₃)CH₂CH₃ H 1.992 2-9 —CH(CH₂CH₃)₂ H 2.075 2-10—CH₂CH₂CH₂N(CH₃)₂ H 0.413 2-11 —CH₂CH₂OCH₃ H 0.217 2-12 —NH—Ph H 1.7372-13 —Ph(2-OH) H 1.779 2-14 —CH₂CH₂N(CH₃)₂ H 0.361 2-15—Ph(3-OCH₃-4-OCH₃-5-OCH₃) H 1.305 2-16 cyclohexyl CH₃ 2.213 2-17—CH₂CH₂CH₂CH₃ CH₃ 1.836 2-18 —CH₂CH₂CH₃ CH₂CH₂CH₃ 2.250

In another embodiment of the present invention, presently preferredbenzimidazole derivatives are those of Formula A-3 where R₁ is selectedfrom those groups listed in Table 3:

TABLE 3 Cpd. No. R₁ LogP 3-1 —CH₂CH₂CH₂CH₂Cl 2.239 3-2 —CH₂CH₂OCH₂CH₂Cl1.571 3-3 —CH₂CH═CH₂ 1.772 3-4 —(CH₂CH₂O)₂CH₂CH₃ 1.045 3-5—CH₂CH₂OCH₂CH₂OH 0.424 3-6 —CH₂CH₂CH═CH₂ 2.024 3-7 —CH₂Ph 2.808 3-8—CH₂CH₂N(CH₃)₂ 1.011 3-9 —CH₂CH₂CH₂Cl 1.788 3-10 —CH₂CH═CHCH₂OH 1.1213-11 —CH₂CH₂CH₂CH₂CH₂OH 1.488 3-12 —CH(CH₂Cl)₂ 2.510 3-13—CH₂CH(CH₃)CH₂C(CH₃)₃ 3.802 3-14 —CH₂CF₂CF₃ 2.841 3-15 —CH(CH₂F)₂ 1.4233-16 —CH(CH₃)(cyclopropyl) 2.155 3-17 —CH₂CH₂F 0.542 3-18 —CH(CH₂Br)₂2.636 3-19 —CH₂CH(CH₃)CH₂CH₃ 2.256 3-20 —CH₂CH₂CH(CH₃)CH₂C(CH₃)₃ 4.1263-21 —CH₂CH₂CH(CH₃)CH₂CH₂CH═C(CH₃)₂ 4.048

In a further embodiment, a preferred compound of the invention is ofFormula A-4 where R₁ is —Ph(3-OCH₃-4-OCH₃-5-OCH₃) (Cpd. No. 4-1;LogP=1.955).

In yet another embodiment, a preferred compound is of Formula A-5 whereR₁ is —CH₂CH(CH₃)CH₂C(CH₃)₃ (Cpd. No.5-1; LogP=3.062).

C. Screening Assays

Screening assays for determining those cancers susceptible to treatmentusing compounds of the present invention include incubating cell linemodels representing specific cancers as set forth, for example, by theNational Cancer Institute, in the presence and absence of suchcompounds. Viability of cells may be determined by the MTT assay(Promega Corp., Madison, Wis. 53711), or the SRB (sulforhodamine B)assay (Skehan, et al., JNCI, 82:13,1107,1990). Susceptibility to saidcompounds exists when viability in the presence of a compound of thepresent invention is less than viability in the absence of suchcompound.

Exemplary cell line models representing specific cancers include, butare not limited to, the following:

Non-small Cell Lung Cancer

NCIH23, NCIH324, NCIH522, A549/ATCC, A549(ASC), CALU1, EKVX, NCIH125M,NCIH226, NCIH520, SKMES1, NCIH322M, NCIH358M, NCIH460, NCIH292, HOP62,HOP18, HOP19, HOP92, LXFL 529, SW1573, LXFS 650L, ML1019, ML1076,ML1045, or UABLG22;

Small Cell Lung Cancer

NCIH69, NCIH146, NCIH82, NCIH524, DMS 114, DMS 273, HOP27, SHP77, orRHOS;

Colon Cancer

HT29, HCC2998, HCT116, LOVO, SW1116, SW620, COLO 205, DLD1, WIDR, COLO320DM, HCT15, CXF 280, KM12, KM20L2, COLO 741, CXF 264L, COLO 746,UABC02, MLI059, CAC02, HT29/PAR, HT29/MDR1, or NB4;

Breast Cancer

MCF7, MCF7/ADRRES, ZR751, ZR7530, MDAMB231/ATCC, HS 578T, UISOBCA1 ,MCF7/ATCC, SKBR3, MDAMB435, MDAN, BT549, T47D, MDAMB231, MAXF 401,BT474, or MDAMB468;

Ovarian Cancer

OVCAR3, OVCAR4, OVCAR5, OVCAR8, A2780, IGROV1, SKOV3, OVXF 899, A1336,or ES2;

Leukemia

P388, P3888/ADR, CCRFCEM, CCRFSB, K562, MOLT4, L1210, HL60(TB),RPMI8226, SR, or K562/ADR;

Fibroblast

IMR90, or CCD19LU;

Renal Cancer

UO31, SN12C, SN12S1, SN12K1, SN12L1, SN12A1, A498, A704, CAKI1, RXF 393,RXF631, 7860, SW156, TK164, 769P, SS78, ACHN, TK10, RXF 486L, UOK57, orUOK57LN;

Melanoma

LOX IMVI, MALME3M, RPMI7951, SKMEL2, SKMEL5, SKMEL28, SKMEL31, UCSD242L, UCSD 354L, M14, M19MEL, UACC62, UACC257, MEXF 514L, or UABMEL3;

Prosiate Cancer

PC3, PC3M, DU145, LNCAP, 1013L, UMSCP1, WIS, JE, RER, MRM, DHM, AG, RB,RVP, FC, WAE, DB/SMC, JCA1, ND1, WMF, TSUPRI, JECA, GDP, T10, WBW, RVP1,or WLL;

CNS Cancer

SNB7, SNB19, SNB44, SNB56, SNB75, SNB78, U251, TE671, SF268, SF295,SF539, XF 498, SW 1088, SW 1783, U87 MG, SF767, SF763, A172, orSMSKCNY;.

Bone/muscle

A204/ATCC, OHS, TE85, A673, CHA59, MHM 25, RH18, RH30, or RD; and

Lymphoma

AS283, HT, KD488, PA682, SUDHL7, RL, DB, SUDHL1, SUDHL4, SUDHL10,NUDUL1, or HUT 102.

D. Chemotherapeutic Agents

Chemotherapeutic agents are generally grouped as DNA-interactive agents,antimetabolites, tubulin-interactive agents, hormonal agents, otheragents such as asparaginase or hydroxyurea, and agents as set forth inTable 3. Each of the groups of chemotherapeutic agents can be furtherdivided by type of activity or compound. Chemotherapeutic agents used incombination with a compound of the present invention or salts thereofmay be selected from any of these groups but are not limited thereto.For a detailed discussion of the chemotherapeutic agents and theirmethod of administration, see Dorr, et al, Cancer Chemotherapy Handbook,2d edition, pages 15-34, Appleton & Lange (Connecticut, 1994) hereinincorporated by reference.

DNA-interactive agents include alkylating agents, e.g., cisplatin,cyclophosphamide, and altretamine; DNA strand-breakage agents, such asbleomycin; intercalating topoisomerase II inhibitors, e.g., dactinomycinand doxorubicin; nonintercalating topoisomerase II inhibitors, such asetoposide and teniposide; and the DNA minor groove binder plicamycin,for example.

The alkylating agents form covalent chemical adducts with cellular DNA,RNA, or protein molecules, or with smaller amino acids, glutathione, orsimilar chemicals. Generally, alkylating agents react with anucleophilic atom in a cellular constituent, such as an amino, carboxyl,phosphate, or sulfhydryl group in nucleic acids, proteins, amino acids,or in glutathione. The mechanism and the role of these alkylating agentsin cancer therapy is not well understood.

Typical alkylating agents include, but are not limited to, nitrogenmustards, such as chlorambucil, cyclophosphamide, isofamide,mechlorethamine, melphalan, uracil mustard; aziridine such as thiotepa;methanesulphonate esters such as busulfan; nitroso ureas, such ascarmustine, lomustine, streptozocin; platinum complexes, such ascisplatin, carboplatin; bioreductive alkylator, such as mitomycin, andprocarbazine, dacarbazine and altretamine.

DNA strand breaking agents include bleomycin, for example.

DNA topoisomerase II inhibitors include the following intercalators,such as amsacrine, dactinomycin, daunorubicin, doxorubicin (adriamycin),idarubicin, and mitoxantrone; nonintercalators, such as etoposide andteniposide, for example.

A DNA minor groove binder is plicamycin, for example.

Antimetabolites interfere with the production of nucleic acids by one oftwo major mechanisms. Certain drugs inhibit production ofdeoxyribonucleoside triphosphates that are the immediate precursors forDNA synthesis, thus inhibiting DNA replication. Certain of the compoundsare analogues of purines or pyrimidines and are incorporated in anabolicnucleotide pathways. These analogues are then substituted into DNA orRNA instead of their normal counterparts.

Antimetabolites useful herein include, but are not limited to, folateantagonists such as methotrexate and trimetrexate; pyrimidineantagonists, such as fluorouracil, fluorodeoxyuridine, CB3717,azacitidine, cytarabine, and floxuridine; purine antagonists includemercaptopurine, 6-thioguanine, fludarabine, pentostatin andribonucleotide reductase inhibitors include hydroxyurea.

Tubulin interactive agents act by binding to specific sites on tubulin,a protein that polymerizes to form cellular microtubules. Microtubulesare critical cell structure units. When the interactive agents bind theprotein, the cell can not form microtubules Tubulin interactive agentsinclude vincristine and vinblastine, both alkaloids and paclitaxel, forexample.

Hormonal agents are also useful in the treatment of cancers and tumors.They are used in hormonally susceptible tumors and are usually derivedfrom natural sources. Hormonal agents include, but are not limited to,estrogens, conjugated estrogens and ethinyl estradiol anddiethylstilbesterol, chlortrianisen and idenestrol; progestins such ashydroxyprogesterone caproate, medroxyprogesterone, and megestrol; andandrogens such as testosterone, testosterone propionate;fluoxymesterone, and methyltestosterone.

Adrenal corticosteroids are derived from natural adrenal cortisol orhydrocortisone. They are used because of their anti-inflammatorybenefits as well as the ability of some to inhibit mitotic divisions andto halt DNA synthesis. These compounds include, but are not limited to,prednisone, dexamethasone, methylprednisolone, and prednisolone.

Leutinizing hormone releasing hormone agents or gonadotropin-releasinghormone antagonists are used primarily the treatment of prostate cancer.These include leuprolide acetate and goserelin acetate. They prevent thebiosynthesis of steroids in the testes.

Antihormonal antigens include, for example, antiestrogenic agents suchas tamoxifen, antiandrogen agents such as flutamide; and antiadrenalagents such as mitotane and aminoglutethimide.

Further agents include the following: hydroxyurea appears to actprimarily through inhibition of the enzyme ribonucleotide reductase, andasparaginase is an enzyme which converts asparagine to nonfunctionalaspartic acid and thus blocks protein synthesis in the tumor.

A listing of currently available chemotherapeutic agents according toclass, and including diseases for which the agents are indicated, isprovided as Table 3A.

TABLE 3A Neoplastic Diseases¹ for which Exemplary Chemotherapeuticagents are Indicated Type of Class Agent Name Disease² AlkylatingNitrogen Mechlore- Hodgkin's disease, non- Agents Mustards thamineHodgkin's lymphomas (HN₂) Acute and chronic Cyclophos- lymphocyticleukemias, phamide Hodgkin's disease, Ifosfamide non-Hodgkin'slymphomas, multiple myeloma, neuro- blastoma, breast, ovary, lung,Wilms' tumor, cervix, testis, soft-tissue sarcomas Melphalan Multiplemyeloma, breast, ovary Chlorambucil Chronic lymphocytic leukemia,primary macroglobulinemia, Hodgkin's disease, non- Hodgkin's lymphomasEstramustine Prostate Ethyleni- Hexamethyl- Ovary mines and melamineMethyl- Thiotepa Bladder, breast, ovary melamines Alkyl Busulfan Chronicgranulocytic Sulfonates leukemia Nitro- Carmustine Hodgkin's disease,non- soureas Hodgkin's lymphomas, primary brain tumors, multiplemyeloma, malignant melanoma Lomustine Hodgkin's disease, non-Hodgkin'slymphomas, primary brain tumors, small- cell lung Semustine Primarybrain tumors, stomach, colon Strepto- Malignant pancreatic zocininsulinoma, malignant carcinoid Triazenes Dacarbazine Malignantmelanoma, Procarbazine Hodgkin's disease, Aziridine soft-tissue sarcomasAnti- Folic Methotrexate Acute lymphocytic metabolites Acid Trimetrexateleukemia, chorio- Analogs carcinoma, mycosis fungoides, breast, head andneck, lung, osteogenic sarcoma Pyrimidine Fluorouracil Breast, colon,stomach, Analogs Floxuridine pancreas, ovary, head and neck, urinarybladder, premalignant skin lesions (topical) Cytarabine Acutegranulocytic Azacitidine and acute lymphocytic leukemias PurineMercaptopurine Acute lymphocytic, Analogs and acute granulocytic,Related and chronic granulocytic Inhibitors leukemias Thioguanine Acutegranulocytic, acute lymphocytic, and chronic granulocytic leukemiasPentostatin Hairy cell leukemia, mycosis fungoides, chronic lymphocyticleukemia Fludarabine Chronic lymphocytic leukemia, Hodgkin's andnon-Hodgkin's lymphomas, mycosis fungoides Natural Vinca VinblastineHodgkin's disease, non- Products Alkaloids (VLB) Hodgkin's lymphomas,breast, testis Vincristine Acute lymphocytic leukemia, neuroblastoma,Wilms' tumor, rhabdomyosarcoma, Hodgkin's disease, non-Hodgkin'slymphomas, small-cell lung Vindesine Vinca-resistant acute lymphocyticleukemia, chronic myelocytic leukemia, melanoma, lymphomas, breastEpipodo- Etoposide Testis, small-cell lung phyllotoxins Teniposide andother lung, breast Hodgkin's disease, non- Hodgkin's lymphomas, acutegranulocytic leukemia, Kaposi's sarcoma Antibiotics DactinomycinChoriocarcinoma, Wilms' tumor, rhabdomyosarcoma, testis Kaposi's sarcomaDaunorubicin Acute granulocytic and acute lymphocytic leukemiasDoxorubin Soft-tissue, osteogenic, 4′-Deoxy- and other sarcomas;doxorubicin Hodgkin's disease, non-Hodgkin's lymphomas, acute leukemias,breast, genitourinary, thyroid, lung, stomach, neuroblastoma BleomycinTestis, head and neck, skin, esophagus, lung, and genitourinary tract;Hodgkin's disease, non- Hodgkin's lymphomas Plicamycin Testis,malignant, hypercalcemia Mitomycin Stomach, cervix, colon, breast,pancreas, bladder, head and neck Enzymes L-Asparaginase Acutelymphocytic leukemia Taxanes Docetaxel Breast, ovarian TaxoidsPaclitaxel Biological Interferon Hairy cell leukemia, Response AlfaKaposi's sarcoma, Modifiers melanoma, carcinoid, renal cell, ovary,bladder, non-Hodgkin's lymphomas, mycosis fungoides, multiple myeloma,chronic granutocytic leukemia Tumor Investigational Necrosis FactorTumor- Investigational Infiltrating Lymphocytes Miscellaneous PlatinumCisplatin Testis, ovary, bladder, Agents Coordination Carboplatin headand neck, lung, Complexes thyroid, cervix, endo- metrium, neuroblastoma,osteogenic sarcoma Anthra- Mitoxantrone Acute granulocytic cenedioneleukemia, breast Substituted Hydroxyurea Chronic granulocytic Urealeukemia, polycythemia vera, essential thrombocytosis, malignantmelanoma Methyl Porcarbazine Hodgkin's disease Hydrazine DerivativeAdreno- Mitotane Adrenal cortex cortical Suppressant Amino- Breastglutethimide Hormones Adrenocorti- Prednisone Acute and chronic andcosteroids lymphocytic leukemias, Antagonists non-Hodgkin's lymphomas,Hodgkin's disease, breast Progestins Hydroxy- Endometrium, breastprogesterone caproate Medroxy- progesterone acetate Megestrol acetateEstrogens Diethylstil- Breast, prostate bestrol Ethinyl estradiolAntiestrogen Tamoxifen Breast Androgens Testosterone Breast propionateFluoxy- mesterone Anti- Flutamide Prostate androgen Gonado- LeuprolideProstate, Estrogen- tropin- Goserelin receptor-positive releasing breasthormone analog ¹Adapted from Calabresi, P., and B. A. Chabner,“Chemotherapy of Neoplastic Diseases” Section XII, pp 1202-1263 in:Goodman and Gilman's The Pharmacological Basis of Therapeutics, Eighthed., 1990 Pergamin Press, Inc.; and Barrows, L. R., “Antineoplastic andImmunoactive Drugs”, Chapter 75, pp 1236-1262, in: Remington: TheScience and Practice of Pharmacy, Mack Publishing Co. Easton, Pa, 1995.;# both references are incorporated by reference herein, in particularfor treatment protocols. ²Neoplasms are carcinomas unless otherwiseindicated.E. Potentiators

A “potentiator,” as used herein, is a material that improves orincreases the efficacy of the benzimidazole derivatives or a salt or aprodrug thereof, or that acts on the immune system as animmunomodulator. Potentiators can be used in combination with a compoundof the present invention. A potentiator may be an antiviral agent. Onesuch potentiator is triprolidine or its cis-isomer. Triprolidine isdescribed in U.S. Pat. No. 5,114,951 (1992, the patent is incorporatedby reference herein). A further potentiator is procodazole, (also named1H-benzimidazole-2-propanoic acid, or β-(2-benzimidazole) propionic acidor 2-(2-carboxyethyl)benzimidazole or propazol). Procodazole is anon-specific immunoprotective agent active against viral and bacterialinfections and may be used in combination with the compounds set forthherein. Procodazole is effective with a compound of the presentinvention, alone in treating cancers, tumors, leukemia or viralinfections, or combined with a chemotherapeutic agent.

Further potentiators include, but are not limited to, propionic acid,salts thereof, or ester thereof; antioxidant vitamins such as vitaminsA, C, E or beta-carotene; abacavir; AI-721 (lipid mixture); amprenavir;Amphotericin B methyl ester: AMPLIGEN® (mismatched RNA); anti-AIDSantibody; anti-human interferon-α antibody; anti-AIDS antibody, ascorbicacid and derivatives thereof; AS-101 (heavy metal basedimmunostimulant); azidothymidine; β-interferon; Bropiriroine; butylatedhydroxytoluene; Ciamexon, Cimetidine; CL-246,738, colony stimulatingfactors, including GM-CSF; Creme Pharmatex (benzalkonium chloride);CS-82 (5-unsubstituted derivative of Zidovudine); Cyclosporin;D-penicillamine (3-mercapto-D-valine); delavirdine; dextran sulphate;dinitrochlorobenzene; efavirenz; erythropoietin; Foscarnet (trisodiumphosphonoformate); fusidic acid; ganciclovir, glucan, glycyrrhizin,HPA23 (ammonium-21-tungsto-9-antimonate); human immunevirus antiviral;hyperimmune gamma-globulin, IMREG®-1, IMREG®-2, low molecular weightsubfractions derived from human leukocyte dialysates; indinavir;interferon-α; interferon-gamma; interleukin-1 or interleukin-2;isoprinosine; Krestin; IC-9018; lamivndine; lentilart; LF-1695;methioine-enkephalin; MINOPHAGEN® C (glycyrrhizin); muramyl tripeptide;naltrexone; nelfinavir; Neutropin; nevirapine; Nonoxinol; ORNIDYL®(eflornithine); non-nucleoside inhibitors of revene transcriptase;nucleoside analogues (ddA, ddC, ddJ, ddT, ddG, AZT, and the like);pentamidine isethionate; Phenytoin; polymannoacetate; Peptide T®(octapeptide sequence); protease inhibitors; Ribavirin; Rifibutin(ansamycin); ritonavir, RNA immunomodulator; rsT4 (recombinant solubleT4), saquinavir; shosaikoto and ginseng; SK-818 (germanium-derivedantiviral); sodium diethylthiocarbarmate, stavudine; stearic acidderivative; suramin and analogues thereof; thymic humoral factor; TP-5;Thymosin fraction 5 and Thymosin 1, Thymostimulin TNF (tumor necrosisfactor), vitamin B preparations; Trimetrexate; UA001; α-interferon oracyclovir, for example.

A compound, or a salt or a prodrug thereof, of the present invention maybe combined with a potentiator and with a chemotherapeutic agent in themethods of the present invention.

F. Dosage

Any suitable dosage may be administered in the methods of the presentinvention. The compound or salt or prodrug thereof chosen for aparticular application, the carrier and the amount will vary widelydepending on the species of the warm blooded animal or human, the typeof cancer, or the particular viral infection being treated, anddepending upon the effective inhibitory concentrations observed in trialstudies. The dosage administered will, of course, vary depending uponknown factors, such as the pharmacodynamic characteristics of theparticular compound, salt, or combination and its mode and route ofadministration; the age, health, or weight of the subject; the natureand extent of symptoms; the metabolic characteristics of the drug andpatient, the kind of concurrent treatment; the frequency of treatment;or the effect desired.

Generally a dosage of as little as about 1-2 milligram (mg) per kilogram(kg) of body weight is suitable, but preferably as little as 10 mg/kgand up to about 10,000 mg/kg may be used. Preferably, a dosage from 15mg/kg to about 5000 mg/kg is used. Most preferably, the dose is between150 mg/kg to about 1000 mg/kg. Doses useful in the treatment of canceror viral infections are 250 mg/kg, 500 mg/kg, 800 mg/kg, 1000 mg/kg,1500 mg/kg, 2500 mg/kg, 3500 mg/kg, 4000 mg/kg, 5000 mg/kg, or 6000mg/kg. Any range of doses can be used. Generally, a compound, saltthereof, prodrug thereof, or combination of the present invention can beadministered on a daily basis one or more times a day, or one to fourtimes a week, either in a single dose or separate doses during the day.Twice-weekly dosing over a period of at least several weeks ispreferred, and often dosing will be continued over extended periods oftime and possibly for the lifetime of the patient. However, the dosageand the dosage regimen will vary depending on the ability of the patientto sustain the desired and effective plasma levels of the compounds ofthe present invention, or salt or prodrug thereof, in the blood.

The compound, salt thereof, prodrug thereof, or combination may bemicronized or powdered so that it is more easily dispersed andsolubilized by the body. Processes for grinding or pulverizing drugs arewell known in the art. For example, a hammer mill or similar millingdevice can be used. The preferred particle size is less than about 100 μand preferably less than 50 μ.

Intravenously, the most preferred doses may range from about 1 to about10 mg/kg/minute during a constant rate infusion.

The dosage for humans is generally less than that used in mice and istypically about {fraction (1/12)} of the dose that is effective in mice.Thus, if 500 mg/kg was effective in mice, a dose of 42 mg/kg would beused in humans. For a 60 kg man, this dose would be 2520 mg.

The compounds and salts and prodrugs thereof of the present inventionare generally safe. The LD₅₀ is high, about 1500 mg/kg given orally inmice and there are no special handling requirements. The compounds canbe given orally, and since they are not very soluble, they arepreferably given in tablet form or as a suspension. Alternatively, whenmicronized to sufficiently small size, they may be and preferably aregiven as an injection.

The compounds and salts and prodrugs thereof of the present inventionmay be administered in a unit dosage form which may be prepared by anymethods known to one of skill in the art in light of the presentdisclosure. Unit dosages may include from 1 milligram to 1000 milligramsof active ingredient. Preferably the dosage unit will contain from about10 mg to about 500 mg active ingredient. The active ingredient isgenerally present in an amount of about 0.5% to about 95% by weightbased on the total weight of the dosage unit.

For intravenous use, preferred dosages may range from about 1 to about10 mg/kg/minute during a constant rate infusion.

A dosage unit may comprise a single compound, or mixtures thereof, withother compounds or other cancer- or viral-inhibiting compounds. Thedosage unit may comprise diluents, extenders, carriers, liposomes, orthe like. The unit may be in solid or gel form such as pills, tablets,capsules and the like or in liquid form suitable for oral, rectal,topical, intravenous injection or parenteral administration or injectioninto or around the treatment site. The range and ratio of benzimidazolederivative, or salt or prodrug thereof, to chemotherapeutic agent or topotentiator will depend on the type of cancer or viral infection beingtreated and the particular chemotherapeutic agent or potentiator.

G. Formulations

Formulations of the present invention include the compound of thepresent invention, a salt thereof or a prodrug thereof and, optionally,a chemotherapeutic agent and, optionally, a potentiator generally mixedwith a pharmaceutically acceptable carrier. A “pharmaceutical carrier”is a pharmaceutically acceptable solvent, suspending agent or vehiclefor delivering a compound of the present invention to the animal orhuman. The carrier may be liquid or solid and is selected with theplanned manner of administration in mind. A “pharmaceuticallyacceptable” component is one that is suitable for use with humans and/oranimals without undue adverse side effects (such as toxicity,irritation, and allergic response) commensurate with a reasonablebenefit/risk ratio.

Oral formulations suitable for use in the practice of the presentinvention include capsules, gels, cachets, tablets, effervescent ornon-effervescent powders or tablets, powders or granules; as a solutionor suspension in aqueous or non-aqueous liquid; or as an oil-in-waterliquid emulsion or a water-in-oil emulsion. The compounds of the presentinvention may also be presented as a bolus, electuary, or paste.

Generally, formulations are prepared by uniformly mixing the activeingredient with liquid carriers or finely divided solid carriers orboth, and then if necessary shaping the product. A pharmaceuticalcarrier is selected on the basis of the chosen route of administrationand standard pharmaceutical practice. Each carrier must be “acceptable”in the sense of being compatible with the other ingredients of theformulation and not injurious to the subject. This carrier can be asolid or liquid and the type is generally chosen based on the type ofadministration being used. Examples of suitable solid carriers includelactose, sucrose, gelatin, agar and bulk powders. Examples of suitableliquid carriers include water, pharmaceutically acceptable fats andoils, alcohols or other organic solvents, including esters, emulsions,syrups or elixirs, suspensions, solutions and/or suspensions, andsolution and or suspensions reconstituted from non-effervescent granulesand effervescent preparations reconstituted from effervescent granules.Such liquid carriers may contain, for example, suitable solvents,preservatives, emulsifying agents, suspending agents, diluents,sweeteners, thickeners, and melting agents. Preferred carriers areedible oils, for example, corn or canola oils. Polyethylene glycols,e.g. PEG, are also preferred carriers.

The formulations for oral administration may comprise a non-toxic,pharmaceutically acceptable, inert carrier such as lactose, starch,sucrose, glucose, methyl cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, mannitol, sorbitol, cyclodextrin,cyclodextrin derivatives, or the like.

Capsule or tablets can be easily formulated and can be made easy toswallow or chew. Tablets may contain suitable carriers, binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, flow-inducing agents, or melting agents. A tablet may be made bycompression or molding, optionally with one or more additionalingredients. Compressed tables may be prepared by compressing the activeingredient in a free flowing form (e.g., powder, granules) optionallymixed with a binder (e.g. gelatin, hydroxypropylmethylcellulose),lubricant, inert diluent, preservative, disintegrant (e.g., sodiumstarch glycolate, cross-linked carboxymethyl cellulose) surface-activeor dispersing agent. Suitable binders include starch, gelatin, naturalsugars such as glucose or beta-lactose, corn sweeteners, natural andsynthetic gums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, or the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, or the like. Disintegrators include, for example, starch,methyl cellulose, agar, bentonite, xanthan gum, or the like. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent.

The tablets may optionally be coated or scored and may be formulated soas to provide slow- or controlled-release of the active ingredient.Tablets may also optionally be provided with an enteric coating toprovide release in parts of the gut other than the stomach.

Exemplary pharmaceutically acceptable carriers and excipients that maybe used to formulate oral dosage forms of the present invention aredescribed in US. Pat. No. 3,903,297 to Robert, issued Sep. 2, 1975,incorporated by reference herein. Techniques and compositions for makingdosage forms useful in the present invention are described in thefollowing references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker& Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms:Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms2nd Edition (1976).

Formulations suitable for topical administration in the mouth whereinthe active ingredient is dissolved or suspended in a suitable carrierinclude lozenges which may comprise the active ingredient in a flavoredcarrier, usually sucrose and acacia or tragacanth; gelatin, glycerin, orsucrose and acacia; and mouthwashes comprising the active ingredient ina suitable liquid carrier.

Topical applications for administration according to the method of thepresent invention include ointments, cream, suspensions, lotions,powder, solutions, pastes, gels, spray, aerosol or oil. Alternately, aformulation may comprise a transdermal patch or dressing such as abandage impregnated with an active ingredient and optionally one or morecarriers or diluents. To be administered in the form of a transdermaldelivery system, the dosage administration will, of course, becontinuous rather than intermittent throughout the dosage regimen.

The topical formulations may desirably include a compound that enhancesabsorption or penetration of the active ingredient through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethylsulfoxide and related analogues.

The oil phase of an emulsion used to treat subjects in the presentinvention may be constituted from ingredients known to one of skill inthe art in light of the present disclosure. An emulsion may comprise oneor more emulsifiers. For example, an oily phase may comprise at leastone emulsifier with a fat or an oil, with both a fat and an oil, or ahydrophilic emulsifier may be included together with a lipophilicemulsifier that acts as a stabilizer. Together, the emulsifier(s), withor without stabilizer(s), make up an emulsifying wax, and the waxtogether with the oil and/or fat make up the emulsifying ointment basethat forms the oily dispersed phase of the cream formulations.

Emulsifiers and emulsion stabilizers suitable for use in the formulationinclude Tween 60, Span 80, cetosteryl alcohol, myristyl alcohol,glyceryl monostearate and sodium lauryl sulphate, paraffin, straight orbranched chain, mono-or dibasic alkyl esters, mineral oil. The choice ofsuitable oils or fats for the formulation is based on achieving thedesired cosmetic properties, the properties required and compatibilitywith the active ingredient.

Compounds of the present invention may also be administered vaginally,for example, as pessaries, tampons, creams, gels, pastes, foams or sprayformulations containing appropriate carriers in addition to the activeingredient. Such carriers are known in the art in light of the presentdisclosure.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising, for example, cocoa butter or asalicylate.

Formulations suitable for nasal administration may be administered in aliquid form, for example, nasal spray, nasal drops, or by aerosoladministration by nebulizer, including aqueous or oily solutions of theactive ingredient. Formulations for nasal administration, wherein thecarrier is a solid, include a coarse powder having a particle size, forexample, of less than about 100 microns, preferably less than about 50microns, which is administered in the manner in which snuff is taken,i.e., by rapid inhalation through the nasal passage from a container ofthe powder held close up to the nose.

Formulations suitable for parenteral administration include aqueous andnon-aqueous formulations isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending systems designed to target the compound to bloodcomponents or one or more organs. The formulations may be presented inunit-dose or multi-dose sealed containers, for example, ampoules orvials. Extemporaneous injections solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described. Parenteral and intravenous forms may also includeminerals and other materials to make them compatible with the type ofinjection or delivery system chosen.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),or related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents and,if necessary, buffer substances. Antioxidizing agents, such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid saltsthereof, or sodium EDTA. In addition, parenteral solutions may containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,or chlorobutanol. Suitable pharmaceutical carriers are described inRemington, cited supra.

The present invention additionally contemplates administering compoundsof the herein described invention for use in the form of veterinaryformulations, which may be prepared, for example, by methods that areconventional in the art in light of the present disclosure.

Useful pharmaceutical dosage formulations for administration of thecompounds of the present invention are illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules arewashed and dried.

Tablets

A large number of tablets are prepared by conventional procedures sothat the dosage unit was 100 milligrams of active ingredient, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 275 milligrams of microcrystalline cellulose, 11 milligrams ofstarch and 98.8 milligrams of lactose. Appropriate coatings can beapplied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection isprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is made isotonic withsodium chloride and sterilized.

Suspension

An aqueous suspension is prepared for oral administration so that each 5ml contains 100 mg of finely divided active ingredient, 200 mg of sodiumcarboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitolsolution, U.S.P., and 0.025 ml of vanillin.

Compounds of the present invention may be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may be coupled with soluble polymersas targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxylpropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinsubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention can be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

H. Method of Treatment

The method of treatment can be any suitable method which is effective inthe treatment of the particular cancer or viral infection that is beingtreated. Treatment includes administering a therapeutically effectiveamount of the compounds of the present invention in a form describedhereinabove, to a subject in need of treatment.

Compounds of the present invention can be administered by any means thatproduces contact of the active agent with the agent's site of action inthe body, for example, suitable means including, but not limited to,oral, rectal, nasal, topical (including transdermal, aerosol, buccal orsublingual), vaginal, parenteral (including subcutaneous, intramuscular,intravenous or intradermal), intravesical, or injection into or aroundthe cancer or site of viral infection. They can be administered by anyconventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutics. Preferably, compounds of the presentinvention are administered as a pharmaceutical formulation comprising atleast one compound of the present invention, as defined above, togetherwith one or more pharmaceutically acceptable carriers. It can beco-administered in the form of a tablet or capsule, as an agglomeratedpowder, or in a liquid form, or as a liposome.

The preferred route will vary with the condition and age of therecipient, virus or cancer being treated nature of the disorder, orseverity of disorder. It is believed that oral administration, orparenteral treatment is the preferred method of administering thecompounds to subjects in need thereof.

In each of the above-described methods, the administering may be invivo, or may be ex vivo. In vivo treatment is useful for treatingdiseases in a mammal, preferably the mammal is a human; and ex vivotreatment is useful for purging body fluids, such as blood, plasma, bonemarrow, and the like, for return to the body. The nation's blood supplyis currently tested for antibodies to HIV. However, the test is stillimperfect and samples that yield negative tests can still contain HIVvirus. Treating blood and blood products with the compounds of thepresent invention can add an extra margin of safety to kill anyretrovirus that may have gone undetected. Body tissue may be internal orexternal to an animal body, or, for example, may be the surface skin ofthe animal.

I. Combination Therapy

Compounds of the present invention may additionally be combined withchemotherapeutic agents and/or potentiators to provide a combinationtherapy. Combination therapy is intended to include any chemicallycompatible combination of a compound of the present invention with othercompounds of the present invention or other compounds outside of thepresent invention, as long as the combination does not eliminate theactivity of the compound of the present invention. For example, one ormore compounds may be combined with a potentiator or with achemotherapeutic agent. In the case of retroviral infection, acombination therapy with nucleoside analogues such as AZT, nonnucleosidereverse transcriptase inhibitors, TC-3, or protease inhibitors iscontemplated by the present invention. In the case of hepatitis,acyclovir, famciclovir or valacyclovir, Ribavirin, interferon, orcombinations of Ribavirin and interferon or beta globulin iscontemplated as a combination therapy. For herpes, a recombinant alphainterferon can be used as a combination therapy. The active agent can becoadministered, for example, in the form of a tablet or capsule,liposome, as an agglomerated powder, or in a liquid form. The amount ofchemotherapeutic agent or potentiator used can be lower than that of thebenzimidazole derivative. It will be present in a dosage unit in anamount that provides an operative combination with the benzimidazolederivative. The dosage of the chemotherapeutic agent or the potentiatorcan range from about 0.5 mg/kg body weight to about 400 mg/kg bodyweight.

Combination therapy can be sequential, that is the treatment with oneagent first and then the second agent, or it can be treatment with bothagents at the same time. The sequential therapy can be within areasonable time after the completion of the first therapy beforebeginning the second therapy. The treatment with both agents at the sametime can be in the same daily dose or in separate doses. For example,treatment with one agent on day 1 and the other on day 2. The exactregimen will depend on the disorder being treated, the severity of thedisorder, and the response to the treatment.

In addition to the use of chemotherapeutic agents and potentiators, abenzimidazole derivate or a salt or a prodrug thereof can be combinedwith a fungicide or an herbicide. Preferred herbicides and fungicidesinclude carbendazim, fluoconazole, benomyl, glyphosate, andpropicodazole.

J. Pharmaceutical Kits

The present invention also includes pharmaceutical kits useful, forexample, for the treatment of cancer or viral infection. The kitscomprise one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thepresent invention or a salt or a prodrug thereof. Such kits can furtherinclude, if desired, one or more of various conventional pharmaceuticalkit components, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instruction, suchas e.g. printed instructions either as inserts or as labels or the like,the instruction indicating quantities of the components to beadministered, guidelines for administration, and/or guidelines formixing the components, can also be included with the kit.

K. Studies

The following studies were performed to test the effectiveness of thebenzimidazole derivatives of the present invention against certaincancers and viral infections.

Colon and Melanoma Tumor Cells Test

The following cell culture tests were performed to test the toxicity ofbenzimidazole derivative compounds of the present invention on colon andmelanoma tumor cells. The viability of the cells were tested by lookingat MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide)reduction. MTT assay is a well known measure of cell viability.

The colon tumor cells (HT29) and the melanoma cells (B16 murinemelanoma) were seeded (1000-2000 cells) into each well of a 96-wellmicrotiter plate and allowed to grow. Twenty-four hours later,increasing concentrations of each benzimidazole derivative were added tothe plates and the cells were allowed to incubate for 3-6 days in thepresence of the drugs. MTT reagent was then added to the wells andallowed to incubate for 4 hours at 37° C., after which the formazanmetabolite was solubilized with acidic isopropanol and the absorbancewas read. Experimental controls included blank wells to which no cellswere added (zero point of formazan absorbance) and control wells towhich no drug was added (highest level of formazan absorbance). Eachdrug concentration was tested in duplicate and the resulting averageabsorbance was plotted against drug concentration using the EZ-ED50computer program on a personal computer interfaced to the microtiterplate reader. The program fit the resulting curves to a four-parameterequation:$Y = {\frac{A_{\max} - A_{\min}}{\left( {1 + \frac{X}{IC50}} \right)^{n}} + A_{\min}}$where A_(max) and A_(min) are, respectively, the absorbances in theabsence and presence of highest drug concentration, X is the drugconcentration and Y is the absorbance at that concentration, n is theslope of the curve, and IC₅₀ is the concentration of drug that gives 50%growth inhibition. The IC₅₀ value is then derived from this equation byEZ-ED50. The IC₅₀ values for growth inhibition of both B16 and HT29cancer cell lines are reported in Table 4 below (Y=H unless otherwiseindicated).

TABLE 4 IC₅₀ (μM) Cpd. No. Murine Melanoma Human Colon Carcinoma 1-120.1 15.8 1-2 14.0 26.3 2-1 530.3 397.8 2-2 80.5 121.0 2-3 2.9 1.6 2-447.2 35.7 2-5 5.9 5.1 2-6 0.84 0.50 2-7 0.41 0.42 2-8 5.0 4.9 2-9 0.37228.3 2-10 553.2 446.9 2-11 30.5 17.1 2-12 271.3 25.4 2-13 2.8 2.3 2-14402.7 158.0 2-15 6.1 4.2 2-16 0.32 0.23 2-17 4.6 2.5 2-18 9.4 3.1 3-10.011 0.010 3-2 0.082 0.036 3-3 0.22 0.059 3-4 0.084 0.027 3-5 2.6 — 3-60.044 0.0076 3-7 0.085 0.033 3-8 70.4 48.6 3-9 0.21 0.054 3-10 1.0 0.603-11 248.1 107.4 3-12 0.99 2.1 3-13 0.0046 0.019 3-14 588.2 313.5 3-150.94 0.61 3-16 0.062 0.030 3-17 0.97 0.30 3-18 1.2 2.1 3-19 0.048 0.0123-20 <0.001 0.013 3-21 0.077 0.046 4-1 0.25 0.17 5-1 6.6 7.0Microtubule Inhibition Assay

The benzimidazole derivatives of this invention were evaluated for theirability to inhibit formation of microtubules, following the procedure ofLuduena, R. F. and M. C. Roach (Pharmacol. Ther. 49: 133-152 (1991)).Tubulin was purified from bovine brain by a cycle of assembly anddisassembly, followed by phosphocellulose chromatography and gelfiltration (Fellous, A. et al., Eur. J. Biochem. 78(1): 167-174 (1977)).The assay was performed by preparing a sample of tubulin protein underconditions which promote polymerization into microtubules (Prasad, V. etal., J. Protein Chem. 11(5): 509-515 (1992)), then adding thebenzamidazole derivatives, at 2 μM, and following the time course ofpolymerization. Microtubule polymerization was followed by performingthe reaction in a cuvette and monitoring UV absorbance at 350 nm,allowing direct visualization of the time course of the polymerization.After 30 minutes, polymerization was complete and the percent inhibitionof polymerization was calculated as the final absorbance of the reactiontaken as a percentage of the final absorbance of a controlpolymerization reaction run in parallel without drug added. These dataare reported in Table 5 below.

TABLE 5 Tubulin Polymerization Inhibition Cpd. No. % Inhibition 1-1 381-2 35 2-1 24 2-2 11 2-3 26 2-4 36 2-5 37 2-6 12 2-7 43 2-8 none 2-9 162-10  5 2-11 19 2-12 50 2-13 27 2-14 none 2-15  5 2-16 39 2-17 none 2-1842 3-1 28 3-2 14 3-3 42 3-4 12 3-5 10 3-6 12 3-7 26 3-8 none 3-9 none3-10 none 3-11 50 3-12 11 3-13 28 3-14 23 3-15 45 3-16 44 3-17  8 3-18none 3-19 28 3-20 35 3-21  2 4-1  2 5-1 noneDNA Binding Assay

The DNA binding assay was performed in a manner very similar to that ofthe MTT cell growth inhibition assay above. The assay was based upon theability of the test compounds to displace methyl green (Sigma) from DNAand the resultant hydration of the free methyl green molecule to acolorless derivative (Burres, N. S. et al., J. Nat. Prod. 55(11):1582-1587 (1992); Kim and Nordén, FEBS Lett. 315(1): 61-64 (1993)). Asfor the MTT assay, each drug concentration was assayed in duplicate andthe data were averaged before analysis. Experimental controls in thisassay included wells containing free methyl green solution with no DNA,for fully decolorized background absorbance, and methyl green-DNAcomplex (Sigma) without drug, for the highest possible methyl greenabsorbance. Methyl green-DNA in buffer was added to each well to obtainA₆₅₅ of approximately 0.7. Serial dilutions of drug in buffer were addedand the plates were mixed, then allowed to stand at room temperature for24 hours to allow for displacement and hydration of the free methylgreen. The absorbance at 655 nm was measured as a function of added drugconcentration in an automated microplate reader, and the data werereduced by the computer program EZ-ED50 to derive IC₅₀ values(concentration at which 50% of the methyl green is displaced from DNA).

None of the benzimidazole derivatives listed in Table 4 or 5 showed anyDNA interaction by this assay.

In vivo B16 Murine Melanoma Tumor Model

B6D2F1 mice received interperitoneally (i.p.) inocula of B16 murinemelanoma brei prepared from B16 tumors growing s.c. in mice (Day 0). OnDay 1, mice were randomized into groups, with 20 mice in the controlgroup and 10 mice in each treated group (except there were 8 mice inselected groups given compound 3-13. Treatment with drugs or vehiclecontrol was started on Day 1.

The mean survival times of all groups were calculated and results wereexpressed as mean survival of treated mice/mean survival of control mice(T/C)×100%. A “T/C” value of 150 means that the mice in the treatedgroup lived 50% longer than those of the control group; this issometimes referred to as the increase in life span, or ILS value.

Mice that survived for at least 60 days were considered to be long-termsurvivors, or cures, in the B16 model. The universally accepted cut-offfor activity in this model, which has been used for years by the NCI, isT/C=125. Conventional use of B16 over the years has set the followinglevels of activity:

TIC<125, no activity

T/C=125-150, weak activity

T/C=150-200, modest activity

T/C=200-300, high activity

T/C>300, with long-term survivors=excellent, curative activity.

Three of the four analogs tested were generally inactive against the B16murine melanoma model using the dosing regimen described above. Compound3-1, at 50 mg/kg/i.p., showed weak activity using the NCI's criteria fordefining antitumor activity. In addition, one long-term survivor wasobserved with this compound and dosing regimen. The results arepresented in Table 6, below.

TABLE 6 Benzimidazole Derivatives vs. B16 Murine Melanoma Weight # ofChange # of Toxic Cpd. # Dose/Route¹ Schedule (Day 12) T/C (%) SurvivorsDeaths Cntrl 20 Tween 80/i.p qd × 5 +6.9% 100 0 0 3-1 10 100 mg/kg/i.pqd × 5 +12.9% 108 0 0 3-1 10  50 mg/kg/i.p qd × 5 +7.5% 132 1 0 3-1 10 20 mg/kg/i.v qd × 5 +6.3% 98 0 0 3-1 10  10 mg/kg/i.v qd × 5 +9.3% 97 00 3-6 10 100 mg/kg/i.p qd × 5 +8.9% 118 0 0 3-6 10  50 mg/kg/i.p qd × 5+9.4% 119 0 0 3-6 10  20 mg/kg/i.v qd × 5 +6.5% 99 0 0 3-6 10  10mg/kg/i.v qd × 5 +8.7% 107 0 0 3-13 10 100 mg/kg/i.p qd × 5 +9.8% 75 0 03-13 10  50 mg/kg/i.p qd × 5 +12.5% 94 0 0 3-13  8  5 mg/kg/i.v qd × 5+3.6% 91 0 7 3-13  8  2.5 mg/kg/i.v qd × 5 +11.7% 92 0 0 3-19 10 100mg/kg/i.p qd × 5 +10.8% 124 0 0 3-19 10  50 mg/kg/i.p qd × 5 +9.6% 119 00 3-19 10  40 mg/kg/i.v qd × 5 +2.5% 73 0 6 3-19 10  20 mg/kg/i.v qd × 5+7.8% 106 0 0 ¹i.p = interperitoneally i.v = intravenously

EXAMPLES Example 1

Synthesis of Cpd. No. 1-1

0.100 Grams (0.482 mmol) of methyl 2-amino-5-hydroxybenzimidazolecarbamate and 0.171 g (0.966 mmol) of 3,5,5-trimethylhexanoyl chloridewere mixed in 3 mL dry tetrahydrofuran under argon. The mixture wasstirred at 23° C. for 16 hours and at 40° C. for 1 hour. The mixture wascooled to 23° C. and a precipitate was collected by filtration andrecrystallized from ethyl acetate. The tan powder weighed 0.096 g (0.276mmol, 57.2% yield).

Example 2

Synthesis of Cpd. No. 1-2

0.135 Grams (0.65 mmol) of methyl 2-amino-4-hydroxybenzimidazolecarbamate and 0.150 g (0.65 mmol) of 3,4,5-trimethoxybenzoyl chloridewere mixed in 2 mL dry tetrahydrofuran under argon. The mixture wasstirred at 23° C. for 16 hours and at 40° C. for 1 hour. The mixture wascooled to 23° C. and a solid was collected by filtration andrecrystallized from ethyl acetate. The gray powder weighed 0.128 g(0.318 mmol, 48.9% yield).

Example 3

Synthesis of methyl 5-chlorocarbonyl-1H-benzimidazole-2-carbamate

7.4 mL (12.069 g, 101.4 mmol) thionyl chloride and 1.80 g (7.66 mmol)methyl 5-carboxy-1H-benzimidazole-2-carbamate in 37 mL dry benzene wereheated to reflux under argon for 3.5 hours. The mixture was then cooledto 23° C. and the solvent and excess thionyl chloride were distilledunder reduced pressure. The resulting brown solid was stored undervacuum to remove all traces of thionyl chloride and used in thefollowing Examples without further purification.

Example 4

Synthesis of Cpd. No. 2-14

0.150 Grams (0.591 mmol) of methyl5-chlorocarbonyl-1H-benzimidazole-2-carbamate and 2.0 mL (1.606 g, 18.22mmol) N,N-dimethylethylenediamine were stirred together in 3 mL drytetrahydrofuran under argon for 16 hours at 23° C., then at 40° C. forone hour. The mixture was diluted with 5 mL dichloromethane, washed withsaturated aqueous sodium carbonate, and the organic layer was dried oversodium sulfate, concentrated by evaporation under reduced pressure andcooled on an ice-water bath. The precipitated solid was collected byfiltration and washed with ice-cold ethyl acetate to provide 0.018 g(0.059 mmol, 10.0% yield) of product as a tan powder.

Example 5

Synthesis of Cpd. No. 2-12

0.150 Grams (0.591 mmol) of methyl5-chlorocarbonyl-1H-benzimidazole-2-carbamate and 2.0 mL (2.198 g, 20.33mmol) phenylhydrazine were stirred together in 3 mL dry tetrahydrofuranunder argon for 16 hours at 23° C., then at 40° C. for one hour. Themixture was diluted with 5 mL dichloromethane, washed with saturatedaqueous sodium carbonate, and the organic layer was dried over sodiumsulfate, concentrated by evaporation under reduced pressure and cooledon an ice-water bath. The precipitated solid was collected by filtrationand washed with ice-cold ethyl acetate to provide 0.038 g (0.117 mmol,19.8% yield) of product as a tan powder.

Example 6

Synthesis of Cpd. No. 2-6

To 0.203 g (0.800 mmol) of methyl5-chlorocarbonyl-1H-benzimidazole-2-carbamate was added 2 mL drytetrahydrofuran, followed by 1.0 mL (0.717 g, 7.09 mmol)1,3-dimethylbutylamine under argon. The mixture was stirred for 16 hoursat 23° C., then the precipitated solid was collected by filtration,washed with diethyl ether, and recrystallized from methanol/diethylether to provide 0.157 g (0.493 mmol, 61.6% yield) of product as a whitepowder.

Example 7

Synthesis of Cpd. No. 2-16

To 0.166 g (0.654 mmol) of methyl5-chlorocarbonyl-1H-benzimidazole-2-carbamate was added 2 mL drytetrahydrofuran, followed by 1.0 mL (0.868 g, 7.668 mmol)N-methylcyclohexylamine under argon. The mixture was stirred for 16hours at 23° C., then the precipitated solid was collected byfiltration, washed with diethyl ether, and recrystallized frommethanol/diethyl ether to provide 0.134 g (0.406 mmol, 62.1% yield) ofproduct as a tan powder.

Example 8

Synthesis of Cpd. No. 3-4

0.121 Grams (0.477 mmol) of methyl5-chlorocarbonyl-1H-benzimidazole-2-carbamate and 2.0 mL (1.998 g, 14.89mmol) 2-(2-ethoxyethoxy)ethanol were stirred together under argon for 16hours at 23° C., then at 40° C. for one hour. The mixture was dilutedwith 75 mL dichloromethane, washed with saturated aqueous sodiumcarbonate, and the organic layer was dried over sodium sulfate,concentrated by evaporation under reduced pressure and cooled on anice-water bath. The precipitated solid was collected by filtration andwashed with ice-cold ethyl acetate to provide 0.083 g (0.236 mmol, 49.5%yield) of product as an off-white powder.

Example 9

Synthesis of Cpd. No. 3-5

0.247 Grams (0.974 mmol) of methyl5-chlorocarbonyl-1H-benzimidazole-2-carbamate and 2.0 mL (2.236 g, 21.07mmol) diethylene glycol were stirred together under argon for 16 hoursat 23° C., then at 40° C. for one hour. The mixture was diluted with 75mL dichloromethane, washed with saturated aqueous sodium carbonate, andthe organic layer was dried over sodium sulfate, concentrated byevaporation under reduced pressure and cooled on an ice-water bath. Theprecipitated solid was collected by filtration and washed with ice-coldethyl acetate to provide 0.001 g (0.030 mmol, 3.1% yield) of product asa cream-colored powder.

Example 10

Synthesis of Cpd. No. 3-8

0.151 Grams (0.595 mmol) of methyl5-chlorocarbonyl-1H-benzimidazole-2carbamate and 2.0 mL (1.774 g, 19.90mmol) N,N-dimethylethanolamine were stirred together under argon for 16hours at 23° C., then at 40° C. for one hour. The mixture was dilutedwith 75 mL dichloromethane, washed with saturated aqueous sodiumcarbonate, and the organic layer was dried over sodium sulfate,concentrated by evaporation under reduced pressure and cooled on anice-water bath. The precipitated solid was collected by filtration andwashed with ice-cold ethyl acetate to provide 0.066 g (0.215 mmol, 36.1%yield) of product as a tan powder.

Example 11

Synthesis of Cpd. No. 3-12

0.100 Grams (0.394 mmol) of methyl5-chlorocarbonyl-1H-benzimidazole-2-carbamate and 1.0 mL (1.351 g, 10.47mmol) 1,3-dichloropropanol were stirred together under argon for 2.5hours at 23° C., then at 40° C. for 16 hours. The mixture was dilutedwith 75 mL dichloromethane, washed with saturated aqueous sodiumcarbonate, and the organic layer was dried over sodium sulfate,concentrated by evaporation under reduced pressure and diluted withice-cold diethyl ether. The precipitated solid was collected byfiltration and dried under reduced pressure to provide 0.045 g (0.130mmol, 33.0% yield) of product as an off-white powder.

Example 12

Synthesis of Cpd. No. 4-1

0.135 Grams (0.65 mmol) of methyl 2-amino-5-hydroxybenzimidazolecarbamate and 0.150 g (0.65 mmol) of 3,4,5-trimethoxybenzoyl chloridewere mixed in 2 mL dry tetrahydrofuran under argon. The mixture wasstirred at 23° C. for 16 hours and at 40C for 1 hour. The mixture wascooled to 23° C. and a solid was collected by filtration andrecrystallized from ethyl acetate. The tan powder weighed 0.080 g (0.199mmol, 30.6% yield).

Example 13

Synthesis of Cpd. No. 5-1

To 0.171 g (0.966 mmol) of 3,5,5-trimethylhexanoyl chloride in 3 mL drytetrahydrofuran under argon was added 0.074 g (0.359 mmol) of methyl2-amino-(5-aminobenzimidazole)carbamate. The mixture was stirred at 23°C. for 16 hours and at 40° C. for 1 hour. The mixture was then cooled to23° C. and a precipitate was collected by filtration and recrystallizedfrom ethyl acetate. The white powder weighed 0.055 g (0.159 mmol, 44.3%yield).

1. A method for treating carcinoma, sarcoma, or lymphoma susceptible totreatment in a warm-blooded animal comprising administering to thewarm-blooded animal a therapeutically effective amount of a compound ofthe following formula A-1:

wherein, R₁ is —CONR₁R₂, —OCOR₁ or —NHCOR₁; R is alkyl, haloalkyl,hydroxyalkyl, alkenyl, haloalkenyl, cycloalkyl, cycloalkalkyl,heterocycloalkyl, heterocycloalkalkyl, substituted or unsubstitutedphenyl, substituted or unsubstituted phenylamino, substituted orunsubstituted benzyl, alkoxyalkly, poly(alkoxy)alkyl,hydroxyalkoxyalkyl, hydroxypoly(alkoxy)alkyl, haloalkoxyalkyl,halopoly(alkoxy)alkyl, or aminoalkyl; and R₂ is hydrogen or alkyl, for atime and under conditions effective to treat said carcinoma, sarcoma orlymphoma.
 2. A method according to claim 1 wherein the compound is inthe form of a pharmaceutically acceptable salt thereof.
 3. A methodaccording to claim 2 wherein said pharmaceutically acceptable salt ishydrochloride salt.
 4. A method according to claim 1 wherein thecompound is in the form of a prodrug thereof.
 5. A method according toclaim 1 wherein R is —OCOR₁.
 6. A method according to claim 5 wherein R₁is alkyl or substituted or unsubstituted phenyl.
 7. A method accordingto claim 1 wherein said compound is micronized and is suitable foradministering to said warm-blooded animal by injection.
 8. A methodaccording to claim 1 wherein said compound is administered in an amountof from 10 mg/kg body weight to 10,000 mg/kg body weight.
 9. A methodaccording to claim 1 wherein said compound is administered orally,enterically, intravenously, peritoneally, or by injection.
 10. A methodaccording to claim 1 wherein said compound is administered in apharmaceutically acceptable carrier.
 11. A method according to claim 1wherein the method is for treating carcinoma.
 12. A method according toclaim 11 wherein said carcinoma is melanoma.
 13. A method according toclaim 11 wherein said carcinoma is colon cancer.
 14. A method accordingto claim 11 wherein said carcinoma is breast cancer.
 15. A methodaccording to claim 11 wherein said carcinoma is lung cancer.
 16. Amethod according to claim 11 wherein said carcinoma is pancreaticcancer.
 17. A method according to claim 11 wherein said carcinoma isovarian cancer.
 18. A method according to claim 11 wherein saidcarcinoma is prostate cancer.
 19. A method for treating leukemiasusceptible to treatment in a warm-blooded animal comprisingadministering to the warm-blooded animal a therapeutically effectiveamount of a compound of the following formula A-1:

wherein, R is —OCOR₁; and R₁ is alkyl, haloalkyl, hydroxyalkyl, alkenyl,haloalkenyl, cycloalkyl, cycloalkalkyl, heterocycloalkyl,heterocycloalkalkyl, substituted or unsubstituted phenyl, substituted orunsubstituted phenylamino, substituted or unsubstituted benzyl,alkoxyalkyl, poly(alkoxy)alkyl, hydroxyalkoxyalkyl,hydroxypoly(alkoxy)alkyl, haloalkoxyalkyl, halopoly(alkoxy)alkyl, oraminoalkyl, for a time and under conditions effective to treat saidleukemia.